Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease

Dopaminergic cell loss due to the accumulation of & alpha;-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by & alpha;-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating & alpha;-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, & alpha;-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the & alpha;-synuclein-mediated neuroinflammatory response. Neuroinflammatory mechanisms are implicated in Parkinson disease. Here we identify border-associated macrophages (BAMs), as essential for the & alpha;-synuclein-mediated neuroinflammatory response via class II antigen presentation, and T cell infiltration.